Cancer is characterized by invasive, unrestrained division of genetically aberrant cells. Such cells have lost many of the normal control mechanisms that regulate cell division, such as the requirement for external growth signals, contact growth inhibition, regulation by cell cycle checkpoints, and failure of cellular self-destruct mechanisms (apoptosis) triggered by abnormalities in the cell. Progressive genetic changes result in a cell that, for example, divides based on stimulation of mitogenic pathways in the cell independently of a growth signal from outside the cell, such as an external growth factor. Also, cells with genetic abnormalities would normally be arrested at various points in the cell cycle, whereupon biochemical processes would attempt to repair the damage, or if that were unsuccessful, to begin the orderly destruction of the cell through apoptosis. Cancer cells typically have lost the ability to proceed through apoptosis, leading to the survival of aberrant cells with invasive and proliferative characteristics.
Proliferation of cancer cells requires several functional biochemical processes. One is the ability to duplicate the DNA complement of the cell so that progeny cells will have a blueprint for growth and subsequent proliferation. This process involves the use of the endogenous cellular DNA as a template for the biochemical synthesis of a copy. As DNA is a double helix, this process produces two copies of the DNA, each in the form of a double helix. Each of the progeny cells receives one copy of the DNA.
The genetic material of human cells is not present as a single DNA molecule. Instead it is present as a group of DNA molecules. These molecules are not free-floating in the cellular milieu but rather are associated in a highly structured way with proteins in the nucleus of the cell. Such combination of DNA and nuclear proteins is referred to as chromatin. The partitioning of the chromatin into progeny cells proceeds by a highly organized process of the cell cycle known as mitosis.
Before mitosis, chromatin is in an uncondensed state, so that the genetic material is accessible as a blueprint for protein synthesis. During cell division, however, chromatin changes into a highly structured form consisting of condensed chromosomes. Because the DNA has already been duplicated prior to mitosis, two copies of each chromosome are present. They are attached to each other at a chromosomal feature known as the centromere. The two still-joined duplicate DNA-protein (condensed chromatin) assemblies are referred to as chromatids.
For the two progeny cells to succeed in obtaining one copy of each of the duplicated DNA molecules in the chromatids after mitosis, a proteinaceous fiber known as a spindle fiber (connected to each chromatid at the centromere) serves as a microscopic tether to pull the chromatids apart to opposite poles of the cell. This ultimately results in partitioning of the chromatids into the two progeny cells. The formation of spindle fibers is essential for the completion of mitosis and successful cell division. Consequently, the spindle fibers are one potential target in a strategy to obstruct cancer cell division. (J. A. Hadfield, S. Ducki, N. Hirst, and A. T. McGown, Prog. Cell Cycle Res. 2003, 5, 309-325)
The spindle fiber is composed of the protein tubulin. Tubulin exists in two similar forms, α and β tubulin. These two forms associate to form a dimer of tubulin composed of one molecule each of α and β tubulin, and the dimers then associate to form helical aggregates known as microtubules. The microtubule increases in length by polymerization of dimers of tubulin molecules at one end, whereas the microtubule shortens by loss of tubulin molecules at the other end. The polymerization and depolymerization of tubulin at the spindle fiber is essential for mitosis and the production of progeny cancer cells.
Additional roles of tubulin in cells include both the maintenance of cell shape and spatial organization of cell organelles. Failure of the former can lead to another possible anticancer action (in addition to inhibiting mitosis) of the anticancer agents based on interference with microtubule dynamics, namely the collapse of the microvasculature that provides the blood supply to the central regions of the tumor, precipitating dramatic necrosis of all but the peripheral regions of the tumor.
One class of anticancer agents in use therapeutically consists of tubulin polymerization/depolymerization inhibitors. Their mode of action is typically by interaction with tubulin molecules, resulting either in (1) a molecular complex that no longer has the ability to interact with other tubulin molecules required for polymerization of tubulin, or (2) stabilization of the tubulin molecules and preventing the depolymerization of the microtubule. Both modes of action render the spindle fiber unable to carry out its function in cell division. Anticancer compounds such as the vinca alkaloids prevent polymerization of tubulin, whereas anticancer taxanes prevent the depolymerization of tubulin. Both processes result in failure of mitosis. Cancer cells are typically more sensitive to such agents than normal cells are, and design of even more specific antimitotic agents may be based on different variants of tubulin (isotypes) present in cells. (J. T. Huzil, R. F. Ludueña, and J. Tuszynski, Nanotechnol. 2006, 17, S90-S100)
Chalcones are potent antimitotic agents of plant origin. (L. Ni, C. Q. Meng, and J. A. Sikorski, Expert Opin. Ther. Patents 2004, 14(12), 1669-1691; R. J. Anto, K. Sukumaran, G. Kuttan, M. N. A. Rao, V. Subbaraju, and R. Kuttan, Cancer Lett., 1995, 97, 33-37) Synthetic ones designed for anticancer testing are structurally similar to antimitotic agents such as colchicine and Combretastatin A-4, as shown below:

The synthetic chalcone shown above with colchicine and Combretastatin A-4 is designed particularly to associate noncovalently with tubulin. The pattern of ring substitution with OCH3 and OH groups is thought to be important in this association with tubulin, and the CH3 group on the enone C═C is believed to confer stability on the s-trans conformation (i.e., trans at the single bond between O═C and C═C), as is shown. The s-trans conformation is thought to have enhanced ability to associate with tubulin.
Chalcones may also bear heterocyclic groups, as in the case of the three furans, thiophene, two pyridines, indole, and two quinoline groups shown below (F. Herencia, M. L. Ferrándiz, A. Ubeda, J. N. Dominguez, J. E. Charris, G. M. Lobo, and M. J. Alcaraz, Bioorg. Med. Chem. Lett. 1998, 8, 1169-1174; M. L. Edwards, D. M. Stemerick, and P. S. Sunkara, J. Med. Chem. 1990, 33(7), 1948-1954; N.-H. Nam, Y. Kim, Y.-J. You, D.-H. Hong, H.-M. Kim, and B.-Z. Ahn, Eur. J. Med. Chem. 2003, 38, 179-187):

Derivatives of chalcones include structures such as their corresponding flavones, where the C═C—C═O of the parent chalcone (from which the structure is derived) becomes part of a fused ring system. Saturation of the C═C yields the corresponding flavanone derivative of a chalcone. (M. López-Lázaro, Curr. Med. Chem.—Anti-Cancer Agents 2002, 2, 691-714; T. Akihisa, H. Tokuda, M. Ukiya, M. Iizuka, S. Schneider, K. Ogasawara, T. Mukainaka, K. Iwatsuki, T. Suzuki, and H. Nishino, Cancer Lett. 2003, 201, 133-137) and pyrazoles (R. LeBlanc, J. Dickson, T. Brown, M. Stewart, H. N. Pati, D. VanDerveer, H. Arman, J. Harris, W. Pennington, H. L. Holt, Jr., and M. Lee, Bioorg. Med. Chem. 2005, 13, 6025-6034), examples of which are shown below:

There are several disadvantages inherent in conventional antimitotic inhibitors of tubulin polymerization and/or depolymerization. One is reversibility of binding of the antimitotic agent to tubulin and/or microtubules. Others include the development of drug resistance by the tumor, toxicity to the patient, and limited solubility/bioavailability through oral, parenteral, or other routes of administration to the patient. Development of drug resistance by a tumor results in resumption of growth of the tumor and increase in tumor size and tumor burden on the patient, often with fatal results. Toxicity to the patient results in limitations on the dose that can safely be administered (maximum tolerated dose, MTD), thus limiting the achievable antitumor effect of the compound. Limited solubility of the antimitotic agent limits the concentration of the agent that can be delivered to the tumor through typical means of administration (e.g., dissolved in the bloodstream).